A sensitive and inexpensive yeast bioassay for the mycotoxin zearalenone and other compounds with estrogenic activity.
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Zearalenone (ZON) is a nonsteroidal estrogenic mycotoxin produced by plant-pathogenic species of Fusarium. As a consequence of infection with Fusarium culmorum and Fusarium graminearum, ZON can be found in cereals and derived food products. Since ZON is suspected to be a cause of human disease, including premature puberty syndrome, as well as hyperestrogenism in farm animals, several countries have established monitoring programs and guidelines for ZON levels in grain intended for human consumption and animal feed. We developed a low-cost method for monitoring ZON contamination in grain based on a sensitive yeast bioassay. The indicator Saccharomyces cerevisiae strain YZRM7 is unable to grow unless an engineered pyrimidine biosynthetic gene is activated by the expressed human estrogen receptor in the presence of exogenous estrogenic substances. Deletion of the genes encoding ATP-binding cassette (ABC) transporters Pdr5p and Snq2p increases net ZON uptake synergistically. Less than 1 microg of ZON per liter of medium is sufficient to allow growth of the indicator strain. To prevent interference with pyrimidines potentially present in biological samples, we also disrupted the genes FUR1 and URK1, blocking the pyrimidine salvage pathway. The bioassay strain YZRM7 allows qualitative detection and quantification of total estrogenic activity in cereal extracts without requiring further cleanup steps. Its high sensitivity makes this assay suitable for low-cost monitoring of contamination of maize and small grain cereals with estrogenic Fusarium mycotxins. (+info)
Biotransformation of the mycotoxin, zearalenone, to a non-estrogenic compound by a fungal strain of Clonostachys sp.
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Zearalenones are mycotoxins with estrogenic activity consisting of a resorcinol moiety fused to a 14-membered macrocyclic lactone and are produced by various Fusarium species. We found that Clonostachys rosea IFO 7063 was effectively capable of converting zearalenone (1) to cleavage product (2), 1-(3,5-dihydroxyphenyl)-10'-hydroxy-1'E-undecene-6'-one. Moreover, cleavage product 2 did not show potent estrogenic activity like that of 1 and 17beta-estradiol in the human breast cancer MCF-7 cell proliferation assay. (+info)
A resorcylic acid lactone, 5Z-7-oxozeaenol, prevents inflammation by inhibiting the catalytic activity of TAK1 MAPK kinase kinase.
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TAK1, a member of the mitogen-activated kinase kinase kinase (MAPKKK) family, participates in proinflammatory cellular signaling pathways by activating JNK/p38 MAPKs and NF-kappaB. To identify drugs that prevent inflammation, we screened inhibitors of TAK1 catalytic activity. We identified a natural resorcylic lactone of fungal origin, 5Z-7-oxozeaenol, as a highly potent inhibitor of TAK1. This compound did not effectively inhibit the catalytic activities of the MEKK1 or ASK1 MAPKKKs, suggesting that 5Z-7-oxozeaenol is a selective inhibitor of TAK1. In cell culture, 5Z-7-oxozeaenol blocked interleukin-1-induced activation of TAK1, JNK/p38 MAPK, IkappaB kinases, and NF-kappaB, resulting in inhibition of cyclooxgenase-2 production. Furthermore, in vivo 5Z-7-oxozeaenol was able to inhibit picryl chloride-induced ear swelling. Thus, 5Z-7-oxozeaenol blocks proinflammatory signaling by selectively inhibiting TAK1 MAPKKK. (+info)
S14-95, a novel inhibitor of the JAK/STAT pathway from a Penicillium species.
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In a search for new inhibitors of the IFN-gamma mediated signal transduction in HeLa S3 cells using secreted alkaline phosphatase (SEAP) as reporter gene, a novel compound, designated as S14-95 was isolated from fermentations of the imperfect fungus Penicillium sp. 14-95. The compound inhibits the IFN-gamma mediated expression of the reporter gene with IC50 values of 2.5 to approximately 5 microg/ml (5.4 to approximately 10.8 microM). Furthermore the compound inhibited the expression of the proinflammatory enzymes COX-2 and NOS II at 5 microg/ml (10.8 microM) in LPS/IFN-gamma stimulated J774 mouse macrophages. Studies on the mode of action of the compound revealed that the inhibition of the IFN-gamma dependent signaling pathway is caused by an inhibition of the phosphorylation of the STAT1alpha transcription factor. In addition, S14-95 inhibited the activation of the p38 MAP kinase, which is involved in the inducible expression of many proinflammatory genes. (+info)
Betagamma-dehydrocurvularin and related compounds as nematicides of Pratylenchus penetrans from the fungus Aspergillus sp.
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The new nematicidal compound, betagamma-dehydrocurvularin (1), together with three known compounds, alphabeta-dehydrocurvularin (2), 8-beta-hydroxy-7-oxocurvularin (3) and 7-oxocurvularin (4), were isolated from the culture filtrate and mycelial mats of Aspergillus sp. The structures of 1-4 were established by spectroscopic methods including 2D NMR. The biological activities of 1-4 were examined by bioassays with root-lesion nematodes, and lettuce and rice seedlings. (+info)
Mycotoxins.
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Mycotoxins are secondary metabolites produced by microfungi that are capable of causing disease and death in humans and other animals. Because of their pharmacological activity, some mycotoxins or mycotoxin derivatives have found use as antibiotics, growth promotants, and other kinds of drugs; still others have been implicated as chemical warfare agents. This review focuses on the most important ones associated with human and veterinary diseases, including aflatoxin, citrinin, ergot akaloids, fumonisins, ochratoxin A, patulin, trichothecenes, and zearalenone. (+info)
Mycotoxins and reproduction in domestic livestock.
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Molds are parasitic plants that are ubiquitous in livestock feedstuffs. Even though molds themselves reduce the quality of grains, their synthesis of chemical substances termed mycotoxins causes the greatest monetary loss to the animal industry. Five major mycotoxins that impair growth and reproductive efficiency in North America are aflatoxins, zearalenone, deoxynivalenol, ochratoxin, and ergot. Aflatoxins are produced by Aspergillus flavus and Aspergillus parasiticus. Consumption of grains containing aflatoxins by swine affects reproduction indirectly by reducing feed intake and growth. In swine, aflatoxins impair liver and kidney function, delay blood clotting, increase susceptibility to bruising, and interfere with cellular humoral immune systems. Ruminants are comparatively resistant to aflatoxicosis, but presence of aflatoxins in milk of dairy cows is closely monitored for human safety. Depending on environmental conditions, Fusarium roseum can produce either zearalenone or deoxynivalenol. Days 7 to 10 postmating seem to be a critical period of gestation for zearalenone to exert its detrimental actions on early embryonic development. Presence of deoxynivalenol in swine feedstuffs decreases feed intake, causes feed refusal, and induces occasional vomiting. Several species of Penicillium and Aspergillus produce ochratoxin, a mycotoxin that causes necrosis of kidney tissue. Ergot alkaloids produced by Claviceps purpurea on wheat can cause reproductive problems and are associated with lactational failure in swine. Various methods have been developed to remove mycotoxins from infected feedstuffs. Chemical analyses in laboratories as well as diagnostic kits suitable for use at the elevator or farm can be used successfully to identify which mycotoxins are present in suspect feedstuffs. (+info)
Toxin production by Fusarium species from sugar beets and natural occurrence of zearalenone in beets and beet fibers.
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Fifty-five Fusarium isolates belonging to nine species were collected from fungus-invaded tissue of stored sugar beets and identified as F. acuminatum (11 isolates), F. avenaceum (1 isolate), F. culmorum (1 isolate), F. equiseti (23 isolates), F. graminearum (4 isolates), F. oxysporum (1 isolate), F. solani (4 isolates), F. sporotrichioides (7 isolates), and F. subglutinans (2 isolates). All isolates were cultured on autoclaved rice grains and assayed for toxicity by feeding weanling female rats the ground-rice cultures of the isolates in a 50% mixture with a regular diet for 5 days. Fifty-eight percent of the isolates were acutely toxic to rats, 26% caused hematuria, 18% caused hemorrhages, and 29% caused uterine enlargement. In most cases, toxicity could not be accounted for by the known toxins found. The following mycotoxins were found in extracts of the rice cultures: zearalenone (22 to 6,282 micrograms/g), chlamydosporol (HM-8) (68 to 4,708 micrograms/g), moniliformin (45 to 400 micrograms/g), deoxynivalenol (10 to 34 micrograms/g), 15-acetyldeoxynivalenol (5 to 10 micrograms/g), diacetoxyscirpenol (22 to 63 micrograms/g), monoacetoxyscirpenol (21 to 26 micrograms/g), scirpenetriol (24 micrograms/g), T-2 toxin (4 to 425 micrograms/g), HT-2 toxin (2 to 284 micrograms/g), neosolaniol (2 to 250 micrograms/g), and T-2 tetraol (4 to 12 micrograms/g). F. equiseti was the predominant species found on visibly molded beets in the field. Six of 25 moldy sugar beet root samples collected in the field contained zearalenone in concentrations ranging between 12 and 391 ng/g, whereas 10 samples from commercial stockpiles were negative for zearalenone.(ABSTRACT TRUNCATED AT 250 WORDS) (+info)